Leo E. Hollister
Veterans Administration Medical Center
and Stanford University School of Medicine,
Palo Alto, California
Copyright © 1986
by The American Society for Pharmacology
and Experimental Therapeutics
TABLE OF CONTENTS
II. Acute and chronic effects of cannabis in humans
A. Acute studiesIII. Possible adverse effects of cannabis on health
B. Chronic studies
A. ImmunityIV.Therapeutic Uses
B. Chromosomal damage
C. Pregnancy and fetal development
D. Cell metabolism
1. Acute panic reaction
2. Toxic delirium
3. Acute paranoid states
7. Amotivational syndrome
8. Residual psychomotor impairment
9. Brain damage
F. Tolerance and dependence
1. Cross toleranceG. Endocrine and metabolic
2. Physical dependence
H. Lung problems
J. Eye problems
L. Possible accumulation
M. Effects on driving an automobile
A. Antiemetic for patients in cancer therapyV. Summary
D. Muscle relaxant
F. Bronchial asthma
H. Miscellaneous uses
2. Abstinence syndromes due to central nervous system depressants
3. Antineoplastic activity
4. Antimicrobial activity
6. Appetite stimulant
The modern era of research into the effects of cannabis in man began less than 20 years ago. Many issues about its health hazards, as they are with all drugs, remain controversial and ambiguous. Many adverse reactions to drugs were not recognized until after much exposure had occurred. Often these are idiosyncratic or allergic reactions. On the other hand, adverse reactions due to the extensions of the pharmacological action of a drug may be recognized both early and late. A similar pattern holds for cannabis.
The ambiguity currently surrounding the health hazards of cannabis may be attributed to a number of factors besides those which ordinarily prevail. First, it has been difficult to either prove or disprove health hazards in man from animal studies. When such studies of cannabis reveal possible harmful effects, the doses used are often large and the treatment is generally short. Second, cannabis is still used mainly by young persons in the best of health. Fortunately, the pattern of use is more often one of intermittent rather than regular use, the doses of drug usually being relatively small. This factor might lead to an underestimation of the potential impact of cannabis on health. Third, cannabis is often used in combination with tobacco and alcohol, among licit drugs, as well as a variety of other illicit drugs. Thus, potential health hazards from cannabis may be difficult to distinguish from those of concomitantly used drugs. Finally, the whole issue of cannabis use is so laden with emotion that serious investigations of health hazards of the drug have been colored by the prejudices of the experimenter, either for or against the drug as a potential hazard to health.
Assessment of the therapeutic potentials of marijuana is also clouded by prejudices, either for or against the drug. Virtually every claim of therapeutic benefit made for marijuana is for a condition for which there are already many effective treatments. Thus, to justify the use of the new agent, it must be subjected to the same elements of proof as a brand-new drug. Thus far, none of the potential indications has been officially recognized.
This report will focus on three main areas: (a) acute and chronic effects of cannabis in humans; (b) issues regarding its possible adverse effects on health, including its effects on driving ability; and (c) the therapeutic potential of cannabis constituents or synthetic homologs of such constituents.
II. Acute and Chronic Effects of Cannabis in Humans
A. Acute Studies
The availability of synthetic trans-delta-9-tetrahydrocannabinol (THC), the major component of cannabis, and the chemical techniques for quantifying its content in cannabis preparations and in blood have made possible for the first time pharmacological studies which provide some precision in dose. When the material is smoked, as it is most commonly used in North America, a variable fraction of THC is lost by smoke escaping into the air or exhaled from the respiratory dead space. Relatively little is lost by pyrolysis, since it is likely that the cannabinoid is volatilized in advance of the burning segment of the cigarette. The efficiency of the delivery of a dose by smoking has been estimated to be about 18%, but frequent smokers obtain 23%, while infrequent users obtain only 10% (110). THC and marijuana extracts are also active by mouth; the systemic bioavailability of oral administration is only about 6%, one-third that from smoking (130).
When smoked, THC is rapidly absorbed, and effects appear within minutes, If marijuana is of low potency, effects may be subtle and brief. Seldom do they last longer than 2 to 3 h after a single cigarette, although users prolong the effects by repeated smoking. Oral doses delay the onset of symptoms for 30 min to over 2 h, as well as prolonging the span of action of the drug. These time schedules are consistent with knowledge of the pharmacokinetics of the drug. Smoking is similar to i.v. administration in producing maximum plasma concentrations early, while p.o. administration produces slower rises of maximum plasma concentrations, which are also lower than those for smoking (105, 130). Although the route of administration affects the time course and the intensity of cannabis effects in man, the pattern of these effects was well established by early investigators (84, 88).
All observers have commented on the constant increase in pulse rate, often one of the first effects of the drug. Blood pressure tends to fall slightly or remains unchanged; at higher doses, orthostatic hypotension occurs. Conjunctival reddening is also consistently observed. Both this symptom and the increased pulse rate correlate quite well in time with the appearance and duration of psychic effects of the drug, as well as the plasma concentrations of the drug (6). Muscle strength is decreased. Appetite is consistently augmented, along with an increased food intake (80). Observed physiological effects have not included changes in pupil size, respiratory rate, or deep tendon reflexes.
Perceptual and psychic changes are biphasic. An initial period of euphoria or "high" is followed by drowsiness. Time sense is altered, hearing is less discriminant, and vision is apparently sharper with many visual distortions. Depersonalization, difficulty in concentrating and thinking, dream-like states are prominent. Many of these symptoms are similar to those produced by psychotomimetics.
The effects that users derive from cannabis are extremely variable. Some of this variability depends on individual variation in degree of tolerance to the drug, based on prior use. Although it is customary to ascribe some variability to difference in setting, i.e., the type of conditions and surroundings which prevail during the drug use, or to set, i.e., the expectations of the user, proving the effects of either has been difficult. One study indicated that, with pharmacologically active doses of the drug, extreme variations in setting produced little alteration of drug effects, which were clearly different from those produced by placebo (82).
B. Chronic Studies
The effects of chronic use of cannabis are more to the point when considering the issues of its status as a possible social drug. Three large-scale field trials of cannabis users have been implemented, but the results of these trials have done little to allay apprehensions about the possible ill effects of chronic use. Objections have been made about the small samples used, the sampling techniques, and the adequacy of the studies performed.
Jamaica is a country in which cannabis is widely used, under the name ganja. The content of THC in native cannabis is generally high, estimated at several fold that of cannabis generally supplied to users in North America. The average Jamaican user smokes seven to eight cannabis cigarettes a day, such use not being considered deviant in that country. Sixty adult workers, all men, were selected for study. Thirty were ganja smokers, and thirty were not, although the latter may have used cannabis tea. Extensive studies in the hospital revealed no significant physical abnormalities between the two groups. The smokers were found to be at greater risk of functional hypoxia, which might have been due to the fact that tobacco was also used by this group. Smokers claimed to use cannabis to work better, but evidence in a selected subgroup supported slightly decreased performance. The small sample and the fact that impairment may be difficult to detect in unskilled workers make it difficult to be sanguine about these generally negative results (147).
A similar study was done in Costa Rica, another country in which cannabis use is prevalent. Two groups of 80 subjects, users and nonusers, were compared by a variety of clinical and laboratory examinations. Essentially no difference between the two groups was detected (34). Forty-seven chronic users of hashish in Greece were compared with 40 nonusers, focusing primarily on tests of brain damage. No evidence of abnormality in function as judged by a variety of tests could be detected in the hashish group as compared with the others. The hashish users had a higher prevalence of personality disorders, probably unrelated to their use of hashish but possibly contributing to it (49).
If field studies fail to provide evidence of harm from prolonged use of cannabis, it is unlikely that experimental studies will do better, and such has been the case. The results of a 30-day high-dose cannabis study in which doses up to 210 mg of THC per day were administered p.o. to volunteers were most remarkable in how well the subjects tolerated such large doses (93). Tolerance was probably present in most subjects prior to the study, but it was rapidly augmented during it. Under these conditions, a mild withdrawal reaction was found when the drug was abruptly discontinued. Additional unanticipated findings were weight gain, bradycardia, and an absence of psychotomimetic effects. As the amount of drug absorbed from p.o. administration may be small, these results are only partially applicable to smoking.
A longer experimental study in which cannabis was smoked rather than taken p.o. exposed subjects from 35 to 198 mg of THC daily for 78 days. The unique contribution of this study was the discovery of the effects of cannabis in lowering intraocular pressure. Other effects noted were lowering of serum testosterone levels, airway narrowing after heavy use, lack of chromosomal alteration, and unchanged immune responses (35). Other effects of chronic cannabis use are related in a specific publication of the New York Academy of Sciences on chronic cannabis use (31).
In summary, we have a very good idea of the acute effects of cannabis, although these are tempered by the dose of THC, the route of administration of the previous exposure of the user to the drug, and possibly by their past experiences with it. The effects of chronic use are somewhat less certain. Experimental studies suggest that tolerance develops rapidly, that a mild withdrawal reaction may occur, and that some acute effects may be reversed (for instance, a slow heart rate with chronic use rather than a rapid one as seen with acute use). Field studies have failed to detect any major health consequences from chronic heavy use of cannabis, but these studies have many deficiencies, most studies being far too small to pick up unusual or rare consequences that could be of great importance. Nonetheless, one is forced to conclude that cannabis is a relatively safe drug as social drugs go. To date it compares favorably with tobacco and alcohol, if not caffeine. One should bear in mind, however, the very long time that it took to determine the ill effects of these accepted social drugs.